Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

SYMTUZA (NDA-210455)

(COBICISTAT; DARUNAVIR ETHANOLATE; EMTRICITABINE; TENOFOVIR ALAFENAMIDE FUMARATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/31/2023 (SUPPL-23)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of darunavir. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Metabolism and Nutrition Disorders:

Redistribution of body fat

Musculoskeletal and Connective Tissue Disorders:

Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors)

Skin and Subcutaneous Tissue Disorders:

Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions (5.3)]

Renal and Urinary Disorders:

Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, Fanconi syndrome [see Warnings and Precautions (5.6)], crystal nephropathy, and crystalluria

10/20/2022 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of darunavir …

7 Drug Interactions

7.5 Significant Drug Interactions

Table 4: Significant Drug Interactions

For concomitant drug names dabigatran etexilate and edoxaban:

Effect on concentration has changed for both to increased
Clinical Comments updated to read: Refer to the dabigatran etexilate or edoxaban prescribing information for recommendations regarding co-administration. The specific recommendations are based on indication, renal function, and effect of the co-administered P-gp inhibitors on the concentration of dabigatran or edoxaban. Clinical monitoring is recommended when a DOAC not affected by CYP3A4 but transported by P-gp, including dabigatran etexilate and edoxaban, is co-administered with SYMTUZA

04/14/2022 (SUPPL-20)

Approved Drug Label (PDF)

4 Contraindications

Additions and revisions underlined:

Darunavir and cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. SYMTUZA should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Darunavir and cobicistat are both substrates of the cytochrome P450 3A (CYP3A) isoform. Co-administration of SYMTUZA with CYP3A inducers is expected to lower plasma concentrations of darunavir and cobicistat which may lead to loss of efficacy of darunavir and development of resistance. Examples of drugs that are contraindicated for co-administration with SYMTUZA due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions (7.5)] are listed below.

7 Drug Interactions

7.4 Significant Drug Interactions

Additions and revisions underlined:

Table 4 provides examples of established or potentially clinically significant drug interactions with SYMTUZA and recommended steps to prevent or manage these interactions. These recommendations are based on drug interaction trials conducted with the components of SYMTUZA, as individual agents or in combination, or are predicted interactions. No drug interaction trials have been performed with SYMTUZA or with all the components administered together. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs. The table includes potentially significant interactions but is not all inclusive, and therefore the label of each drug that is co- administered with SYMTUZA should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regard to co- administration.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

Additions and revisions underlined:

Do not take SYMTUZA with any of the following medicines:

• alfuzosin

• carbamazepine

• colchicine, if you have liver or kidney problems

• dronedarone

• elbasvir and grazoprevir

• ergot-containing medicines, such as:

- dihydroergotamine

- ergotamine tartrate

- methylergonovine

• ivabradine

• lomitapide

• lovastatin or a product that contains lovastatin

• lurasidone

• midazolam, when taken by mouth

• naloxegol

• phenobarbital

• phenytoin

• pimozide

• ranolazine

• rifampin

• sildenafil, when used for the treatment of pulmonary arterial hypertension (PAH)

• simvastatin or a product that contains simvastatin

• St. John’s wort (Hypericum perforatum), or a product that contains St. John’s wort

• triazolam

Serious problems can happen if you take any of these medicines with SYMTUZA. This is not a complete list of medicines. Therefore, tell your healthcare provider about all medicines you take. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, topical creams, vitamins, and herbal supplements. Some medicines interact with SYMTUZA.

07/29/2021 (SUPPL-16)

Approved Drug Label (PDF)

7 Drug Interactions

7.5 Significant Drug Interactions

Updates to Table 4 under Corticosteroids, please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined

…

Risk Summary

SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Dosage and Administration (2.5)]. A study evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of darunavir and cobicistat in the second and third trimesters compared to the post-partum period (see Data) and [see Clinical Pharmacology (12.3)].

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, available data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir, cobicistat, emtricitabine, or tenofovir alafenamide (TAF) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.

…

Data

Human Data

…

Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of SYMTUZA are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.

Darunavir: Based on prospective reports to the APR of over 960 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 640 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.7% (95% CI: 2.4% to 5.5%) with first trimester exposure to darunavir containing-regimens and 2.5% (95% CI: 1.1% to 4.9%) with second/third trimester exposure to darunavir-containing regimens.

Cobicistat: Based on prospective reports to the APR of over 560 exposures to cobicistat-containing regimens during pregnancy resulting in live births (including over 470 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6% (95% CI: 2.1% to 5.7%) and 1.1% (95% CI: 0.0% to 6.2%) with first and second/third trimester, respectively, to cobicistat-containing regimens.

Emtricitabine: Based on prospective reports to the APR of over 5400 exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including over 3900 exposed in the first trimester and over 1500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) with first trimester exposure to emtricitabine-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) with the second/third trimester exposure to emtricitabine-containing regimens.

Tenofovir alafenamide (TAF): Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) with first and second/third trimester exposure, respectively, to TAF-containing regimens.

…

06/28/2021 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 New Onset or Worsening Renal Impairment

(Additions and/or revisions are underlined)

Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events [see Adverse Reactions (6.1, 6.2)]. SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL per minute.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Renal and Urinary Disorders:

acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome [see Warnings and Precautions (5.6)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(Extensive changes; please refer to labeling)

12/22/2020 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

(Additions and/or revisions underlined)

The concomitant use of SYMTUZA and other drugs may result in known or potentially significant drug interactions which may lead to [see Contraindications (4) and Drug Interactions (7.5)]:

Clinically significant adverse reactions from greater exposures of concomitant drugs.

Clinically significant adverse reactions from greater exposures of SYMTUZA.
Loss of therapeutic effect of the concomitant drugs from lower exposures of active metabolite(s).
Loss of therapeutic effect of SYMTUZA and possible development of resistance from lower exposures of SYMTUZA.

7 Drug Interactions

7.2 Potential for SYMTUZA to Affect Other Drugs

(Newly added information)

Co-administration of SYMTUZA with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 4).

7.5 Significant Drug Interactions

(Table 4 updated with the addition of information regarding platelet aggregation inhibitors clopidogrel and prasugrel)

03/02/2020 (SUPPL-9)

Approved Drug Label (PDF)

6 Adverse Reactions

Clinical Trials Experience

(Newly added subsection)

Clinical Trials in Pediatric Patients

Adverse Reactions in Pediatric Patients Weighing At Least 40 kg

No clinical trials with SYMTUZA were performed in pediatric patients. However, the safety of the components of SYMTUZA was evaluated in pediatric subjects of 12 to less than 18 years of age through clinical trials GS-US-216-0128 (virologically-suppressed, N=7 with weight > or = 40 kg) for darunavir co-administered with cobicistat and other antiretroviral agents, and GS-US-292-0106 (treatment-naïve, N=50 with weight > or = 35 kg) for a fixed-dose combination regimen containing cobicistat, emtricitabine, and tenofovir alafenamide together with elvitegravir. Safety analyses of the trials in these pediatric subjects did not identify new safety concerns compared to the known safety profile of SYMTUZA in adult subjects [see Clinical Studies (14.3)].

8 Use in Specific Populations

Pediatric Use

(Newly added information)

The safety and effectiveness of SYMTUZA for the treatment of HIV-1 infection in pediatric

patients weighing at least 40 kg was established through studies with components of SYMTUZA.

Use of SYMTUZA in this group is supported by evidence from adequate and well-controlled

studies of SYMTUZA in adults with additional pharmacokinetic, safety, and virologic data from

studies of components of SYMTUZA (Trials GS-US-216-0128 and GS-US-292-0106) in pediatric

subjects with HIV-1 infection aged 12 to less than 18 years [see Adverse Reactions (6.1), Clinical

Pharmacology (12.3), and Clinical Studies (14.3)].

The safety and effectiveness of SYMTUZA have not been established in pediatric patients

weighing less than 40 kg.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(Additions and/or revisions underlined)

It is not known if SYMTUZA is safe and effective in children weighing less than 88 pounds (40 kg).

05/30/2019 (SUPPL-4)

Approved Drug Label (PDF)

4 Contraindications

Consolidation of information regarding antianginal and antiarrhythmic drugs into a new category, titled “Cardiac Disorders” and addition of the drug ivabradine. In addition, a new drug class, “Opioid Antagonists” is added with information on naloxegol.

5 Warnings and Precautions

5.5 Immune Reconstitution Syndrome

Additions and/or revisions underlined:

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) …

7 Drug Interactions

Addition of the following statement:

The table includes potentially significant interactions but is not all inclusive.

In Table 4, addition of isavuconazole to “Antifungals”; addition of irinotecan to “Immunosuppressant/neoplastic”; and addition of a new drug class, “Urinary antispasmodics” with information on use of fesoterodine and solifenacin; please refer to label for complete information.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Who should not take SYMTUZA?

Do not take SYMTUZA with any of the following medicines:

Addition of the following:

Ivabradine
Naloxegol

01/25/2019 (SUPPL-1)

Approved Drug Label (PDF)

4 Contraindications

CONTRAINDICATIONS

(Additions and/or revisions are underlined)

Hepatitis C direct acting antiviral: elbasvir/grazoprevir
Lipid modifying agents: lomitapide, lovastatin, simvastatin
…

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

…

An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions irrespective of severity reported in AMBER are presented in Table 1. An overview of the most frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those receiving PREZCOBIX + FTC/TDF are presented in Table 3.

…

Other

PATIENT INFORMATION

(Additions and/or revisions are underlined)

…

Who should not take SYMTUZA?

Do not take SYMTUZA with any of the following medicines:

alfuzosin
carbamazepine
cisapride
colchicine, if you have liver or kidney problems
dronedarone
elbasvir and grazoprevir
ergot-containing medicines, such as:
o dihydroergotamine o ergotamine tartrate o methylergonovine
lomitapide
lovastatin or a product that contains lovastatin
…